Structure–property relations of a unique and systematic dataset of 19 isostructural multicomponent apremilast forms

A unique system of 19 isostructural apremilast multicomponent forms was explored and a correlation between the intrinsic dissolution rates of the new solid forms and the equilibrium solubility of their guest molecules has been discovered.


Crystallography
All presented apremilast multicomponent forms crystallized in tetragonal system with P 41 21 2 space group. This system is unique due to all prepared forms being isostructural. More crystallography details and details from structure solution is in Tab. S1.
Tab. S1: Crystallography details and structure solution details.

Materials and Methods
Apremilast was kindly provided by Zentiva, k.s., as form B (which is used in the original drug product 1 ). The solvents and crystallization partners were obtained from various commercial suppliers and were used as received, without any further purification.

Screening of multicomponent forms of apremilast (single crystal preparation)
Screening was based on available data in scientific literature [5][6][7] . It becomes immediately obvious that the rational way of screening is searching for small aromatic molecules (substituted benzene rings) in Hexafluorobenzene (2) 18 out of the 22 tested molecules resulted in the formation of multicomponent form. Size of the guest molecule appears to be crucial parameter 8 .

Scale up of apremilast multicomponent forms
Scale up to several grams of the new forms was necessary for the measurement and evaluation of properties. Three different approaches were applied during the scale up. All prepared samples were checked by standard solid-state analysis (XRPD, Raman, DSC, NMR) and their powder diffraction pattern was compared to pattern generated from corresponding crystal structures. The solid phase purity was confirmed for all samples.
Which method was used for preparation of each sample is stated in Tab. S2.
Note that for nicotinic acid the preparation of higher amount of the cocrystal was unsuccessful.
Therefore, it was excluded from the correlations.

Results
Additional supporting data that was not shown in the manuscript is presented in this section in a form of figures and tables.

XRPD
XRPD patterns were measured and evaluated to determine formation of a new multicomponent form.
Further, the XRPD patterns of the material used for the measurement and evaluation of properties was compared with patterns calculated from solved crystal structures. This ensures that structure could be properly linked with its properties (Fig. S1). 2 Theta / ° Note that SCXRD measurement was performed at either 120 K/95 K and the XRPD measurement of the prepared multicomponent forms was performed at room temperature. The patterns shown in Fig.   S1 were corrected for equal temperature to simplify the comparison. Differences in peak intensity might be caused by preferential orientation of the crystals during XRPD measurements.
Isostructurality of prepared samples is clearly visible from the XRPD patterns which are very similar.

DSC
DSC was measured to ensure solid phase purity of the prepared samples. Furthermore, melting temperatures of the multicomponent forms were used to correlate with other evaluated properties.
Melting temperature of apremilast used in the original drug product is included as well. Evaluated melting temperatures are summarized in Fig. S2 and Tab. S2. The DSC diagrams used for the evaluation are shown in Fig. S3.  properties. It was also compared with the IDR of apremilast in the original drug product and it was observed that some of the new forms are able to bring substantial pharmaceutical advantages (however, not all of them could be used due to toxicity reasons). IDR values are summarized in Fig.   S4 and Tab. S5.  Measurement of iodobenzene solvate and salicylic acid cocrystal was repeated 10 times, but due to the disc breakage during the IDR measurement it was not possible to obtain usable data for those two solid forms. Therefore, those samples were not included in correlations between intrinsic dissolution rate and other measured quantities. It is interesting to note that IDR of cocrystals was in all cases higher compared to solvates.

EqSol
Equilibrium solubility of the prepared solid forms was measured in pH = 6.8 phosphate buffer with the addition of 0.2% of SDS. The tested solid form was mixed with the buffer and the formed slurry was stirred for 24 h at 750 RPM at room temperature. The solid and liquid phase were separated using centrifugal filtration (4000 RPM) and apremilast content in the liquid phase was analyzed using HPLC. EqSol values were used to correlate with other properties and are summarized in Fig. S5 and Tab. S6.  Phase transformations of the solids during the experiment were considered and the powder samples used for the EqSol experiment were examined via Raman spectroscopy before and after the experiment (Fig. S6). It was observed that solvates are extremely stable over the duration of the experiment (24 hours in dissolution medium). No transformation was observed. Phase stability of cocrystals was varying from sample to sample exhibiting different levels of transformation to apremilast form II 9 . The lowest phase stability was estimated for 4-hydroxybenzoic acid cocrystal with approx. 50% conversion to apremilast form II after 24 h in the dissolution medium. The transformation suggests that there is no complex between the guest molecule and apremilast that would be stable enough to persist in the solution. It also implies that two forms contribute to the equilibrium solubility-the tested cocrystal and apremilast form II. It is interesting to note that conversion to form II appears mostly from multicomponent forms with higher equilibrium solubility as well as IDR (cocrystals). Values for equilibrium solubility of guest molecules in water were find in scientific literature and are summarized in Fig. S7 and Tab. S7. References to scientific literature are also included in Fig. S7 and Tab. S7. Nicotinamide is not included in Fig. S7 to increase clarity, since its solubility in water is much higher compared to the rest of the guest molecules.  All solubility values of guest molecules, as well as references (Tab. S7), were taken from database PubChem (experimental values were used). Nicotinamide was not included into correlations of guest molecule solubility with other properties because its solubility is several orders of magnitude higher compared to the rest of the guest molecules.

CrystalCMP
Crystal CMP was used to compare packing similarity of solved structures. Since many readers might not be familiar with the software used for this purpose, there is a short description of the CrystalCMP software. The CrystalCMP software works differently compared to for example Crystal Packing Bibliography